Transplant-Associated Thrombotic Microangiopathy: Prevalence, Prognostic Factors and Treatment Outcomes in Unrelated Allogeneic Transplant for Hematologic Diseases

Abstract Introduction: Transplant-associated thrombotic microangiopathy (TA-TMA) represents a devastating and life-threatening complication occurring more frequently in allogeneic compared to autologous hematopoietic cell transplantation (HCT). Although it has been a well-recognized syndrome for decades, our understanding in terms of epidemiology and more importantly, treatment options remains unclear. Therefore, we aimed to retrospectively investigate the incidence of TA-TMA in patients undergone HCT from unrelated donors and identify prognostic factors and treatment outcomes. Methods: We enrolled consecutive patients who underwent HCT from unrelated donors from 2003 to 2015. TA-TMA diagnosis was based on EBMT (European Bone Marrow Transplantation) criteria: increased (>4%) schistocytes in peripheral blood, thrombocytopenia, increased lactade dehydrogenase, decreased Hb. Anti-thymocyte globulin (ATG, rabbit) was used as standardised part of the conditioning in almost all patients (total dose of 5-7.5mg/kg). Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine or tacrolimus plus methotrexate in myeloablative and mycophenolate mofetil plus cyclosporine in reduced intensity conditioning transplants. Upon identification of TA-TMA, all possible causative factors were fully investigated. The mainstay of treatment strategy was withdrawal of calcineurin inhibitors, plasma infusion and plasma exchange combined with corticosteroid administration and in refractory cases, humanized anti-CD20 monoclonal antibody (Rituximab). Results: In total, we studied 179 patients, 74 male:105 female, aged 37±14 years, who underwent HCT from matched HLA A/B/C/DRB1 (8/8, n=88) and allele or antigen mismatched (n=91) grafts. Grafts derived from peripheral blood (157), bone marrow (18) and umbilical stem cells (4). Conditioning regimens were myeloablative (139), reduced intensity (28) and toxicity (12). Median follow-up was 11.5 (0.1-147.4) months. TA-TMA was diagnosed in 29 (16.2%) patients, 12 male:17 female, aged 34±12 years, 78 (9-721) days post-HCT for acute leukemia (21), Hodgkin (3) and non-Hodgkin (1), lymphoma, MDS (2), aplastic anemia (1) and MPN (1). Conditioning regimens were myeloablative in 24 (12 based on total body irradiation/TBI) and reduced intensity in 5 patients. Among patients with TA-TMA, 10 (34%) presented severe (grade III-IV) acute GVHD, 15 (52%) extensive chronic GVHD, 12 (41%) bacterial, 2 (7%) fungal and 21 (71%) viral (Cytomegalovirus and/or Epstein-Barr viremia) infectious episodes. In univariate analysis, age, gender, diagnosis, disease phase, previous lines of treatment, conditioning (intensity and TBI-based), ABO and HLA incompatibility, infections, acute and chronic GVHD were studied. The presence of TA-TMA was associated with severe acute and extensive chronic GVHD (p=0.001 and p=0.035 respectively) and TBI-based conditioning (p=0.043). In multivariate analysis, severe acute GVHD was the only independent factor associated with TA-TMA (β=3.4, p=0.038). Regarding treatment outcomes, 8 (28%) patients responded to cyclosporine cessation and plasma infusions. The rest 21 out of 29 patients underwent plasma exchange sessions; 14 (48%) of them responded to plasma exchange treatment. One patient that did not respond to plasma exchange received additional Rituximab treatment and the syndrome resolved. The other 6 (20.6%) patients were refractory and eventually succumbed. Treatment-related mortality was 33.3% (9/29) in TA-TMA patients and was directly associated with refractory microangiopathic syndrome in 6/29. Conclusion: Our results suggest that TA-TMA is not rare in unrelated transplant recipients and can be managed in a portion of patients that respond to cyclosporine cessation and plasma exchange. GVHD was the only independent predictor for the development of TA-TMA and therefore, successful prevention and treatment strategies for GVHD need to be timely employed to prevent complications. More importantly, transplanted patients with refractory microangiopathic syndrome showed increased TRM indicating that conventional treatment is inadequate. Recent data of increased complement activation in TA-TMA pave the way for targeted treatment with complement inhibitors in these patients. Disclosures No relevant conflicts of interest to declare.